1. Field of the Invention
The present invention relates to sustained release ophthalmic compositions that contain water soluble medicaments such as timolol and to the pharmacological use thereof.
2. Description of the Related Art
Ophthalmic compositions have been used as drug delivery systems. For example, commonly assigned U.S. Pat. No. 5,192,535 discloses topical ophthalmic medicament delivery systems for sustained release of medicaments. These systems undergo a substantial increase in viscosity upon contact with tear fluid. In one embodiment, the system is an aqueous suspension which comprises about 0.1% to about 6.5%, by weight, of crosslinked carboxyvinyl polymer and has a pH of about 3 to about 6.5. Upon contact with the tear fluid in the eye, which typically has a pH of around 7.2 to 7.4, the pH increases and the polymer expands thereby increasing the viscosity. The resulting more viscous gel remains in the eye for a longer period of time and thus enhances the sustained release of the medicament. Under this system, the initial viscosity (from 1,000 to 30,000 cps) can be low enough so as to facilitate application to the eye in drop form.
U.S. Pat. No. 5,340,572, also commonly owned, discloses topical ophthalmic medicament delivery systems. In one embodiment, the system contains an aqueous suspension of crosslinked carboxyvinyl polymers and a medicament having multiple amine groups (e.g., an antibiotic), at a pH of 7.5 or more. This suspension can be administered in drop form and remains a gel upon contact with tear fluid so as to provide comfortable and sustained release of the medicament. The delivery system preferably has a viscosity in the range of 5,000 to 30,000 cps, although other viscosities are disclosed. The amount of crosslinked carboxyvinyl polymer is typically within the range of from 0.05% to 10%, by weight, based on the total weight of the aqueous suspension.
While the above-mentioned compositions offer excellent properties, it would be beneficial to improve the release profile of medicaments, especially water soluble medicaments, from an ophthalmic composition having a pH of greater than about 6.7 and a viscosity of less than 5000 cps. In this range of relatively high pH and low viscosity, the amount of crosslinked carboxyvinyl polymer that can be present is limited. Greater amounts of the polymer could be added if either the viscosity was permitted to rise or the pH was reduced. By constraining both of these parameters, the amount of polymer that can be added is restricted. Such constraint may at times be acceptable, but the limited amount of polymer can cause a less desirable release profile; namely, the medicament may not be optimally restrained by the polymer and the medicament may be too rapidly released after administration. Such an insufficient restraint is more prevalent with respect to water soluble medicaments.
In contrast, in the case of medicaments that are substantially water insoluble, the medicament must dissolve before it can be readily released from solution. This dissolving step provides a type of delay that can help to provide sustained release. The delay attributable to the dissolution step is not normally present with water soluble medicaments. Thus, improvements in the sustained release of water soluble medicaments from a low viscosity, low polymer content, high pH ophthalmic composition would be desirable.